tbuckley/cabot-search huggingface dataset:
Medical world pays tribute to the Queen
Authors: Alison Shepherd
Journal: BMJ (2022)

<h3>ABSTRACT</h3> <h3>Background</h3> Dumpsites in low and middle income countries (LMICs) are commonly used for solid waste disposal as opposed to landfills. However, these are naturally unsanitary hence provide ideal conditions for breeding of disease transmitting agents and become predisposing factors for spread of diseases and infections to surrounding communities. This study aimed at determining the Health Effects of Chunga Dumpsite on surrounding communities in Lusaka, Zambia. <h3>Design and Methods</h3> This was a mixed method design and employed a cross sectional approach and case study conducted concurrently. Communities were stratified by distance into Stratum One (within 250 meters radius) and Two (above 250 to 500 meters). Quantitative data were collected from total 200 households thus 100 households from each stratum by using self-administered questionnaires. Qualitative data were collected from Two Key informants from the Local Authority and 15 participants using semi-structured interview guide. Both data were collected from December 22<sup>nd</sup>, 2018 to February 18<sup>th</sup>, 2019. <h3>Results</h3> Results revealed that smoke and various gasses emitted from burning and decomposing waste compromised quality of air in surrounding communities. Communities were infested with flies, mosquitoes and vermin. Consequently, (73.5%) complained of persistent coughing, (65.1%) suffered from malaria, (72.6%) complained of persistent headaches and (62.2%) had frequent diarrhoea cases in stratum one. Respiratory problems were more pronounced at night possibly due to high humidity which hindered pollutants to easily escape. However, these cases reduced drastically in stratum two. <h3>Conclusions</h3> Unsanitary dumpsites in LMICs including Zambia are commonly used as solid waste disposal facilities as opposed to sanitary landfills and become predisposing factors for spread of diseases. Short proximities to dumpsites by unplanned human settlements cause serious environmental challenges leading to public health risks to surrounding communities.
Specialized Pro-Resolving Mediators as Resolution Pharmacology for the Control of Pain and Itch
Authors: Ru-Rong Ji
Journal: The Annual Review of Pharmacology and Toxicology (2022)

Specialized pro-resolving mediators (SPMs), including resolvins, protectins, and maresins, are endogenous lipid mediators that are synthesized from omega-3 polyunsaturated fatty acids during the acute phase or resolution phase of inflammation. Synthetic SPMs possess broad safety profiles and exhibit potent actions in resolving inflammation in preclinical models. Accumulating evidence in the past decade has demonstrated powerful analgesia of exogenous SPMs in rodent models of inflammatory, neuropathic, and cancer pain. Furthermore, endogenous SPMs are produced by sham surgery and neuromodulation (e.g., vagus nerve stimulation). SPMs produce their beneficial actions through multiple G protein–coupled receptors, expressed by immune cells, glial cells, and neurons. Notably, loss of SPM receptors impairs the resolution of pain. I also highlight the emerging role of SPMs in the control of itch. Pharmacological targeting of SPMs or SPM receptors has the potential to lead to novel therapeutics for pain and itch as emerging approaches in resolution pharmacology.
Fibroblast Growth Factor–Based Pharmacotherapies for the Treatment of Obesity-Related Metabolic Complications
Authors: Leigang Jin, Ranyao Yang, Leiluo Geng, Aimin Xu
Journal: The Annual Review of Pharmacology and Toxicology (2022)

The fibroblast growth factor (FGF) family, which comprises 22 structurally related proteins, plays diverse roles in cell proliferation, differentiation, development, and metabolism. Among them, two classical members (FGF1 and FGF4) and two endocrine members (FGF19 and FGF21) are important regulators of whole-body energy homeostasis, glucose/lipid metabolism, and insulin sensitivity. Preclinical studies have consistently demonstrated the therapeutic benefits of these FGFs for the treatment of obesity, diabetes, dyslipidemia, and nonalcoholic steatohepatitis (NASH). Several genetically engineered FGF19 and FGF21 analogs with improved pharmacodynamic and pharmacokinetic properties have been developed and progressed into various stages of clinical trials. These FGF analogs are effective in alleviating hepatic steatosis, steatohepatitis, and liver fibrosis in biopsy-confirmed NASH patients, whereas their antidiabetic and antiobesity effects are mildand vary greatly in different clinical trials. This review summarizes recent advances in biopharmaceutical development of FGF-based therapies against obesity-related metabolic complications, highlights major challenges in clinical implementation, and discusses possible strategies to overcome these hurdles.
Age-Related Perioperative Neurocognitive Disorders: Experimental Models and Druggable Targets
Authors: Odmara L. Barreto Chang, Katherine L. Possin, Mervyn Maze
Journal: The Annual Review of Pharmacology and Toxicology (2022)

With the worldwide increase in life span, surgical patients are becoming older and have a greater propensity for postoperative cognitive impairment, either new onset or through deterioration of an existing condition; in both conditions, knowledge of the patient's preoperative cognitive function and postoperative cognitive trajectory is imperative. We describe the clinical utility of a tablet-based technique for rapid assessment of the memory and attentiveness domains required for executive function. The pathogenic mechanisms for perioperative neurocognitive disorders have been investigated in animal models in which excessive and/or prolonged postoperative neuroinflammation has emerged as a likely contender. The cellular and molecular species involved in postoperative neuroinflammation are the putative targets for future therapeutic interventions that are efficacious and do not interfere with the surgical patient's healing process.
Family History of Prostate and Breast Cancer Integrated with a Polygenic Risk Score Identifies Men at Highest Risk of Dying from Prostate Cancer before Age 75 Years
Authors: Anna Plym, Yiwen Zhang, Konrad H. Stopsack, Yon Ho Jee, Fredrik Wiklund, Adam S. Kibel, Peter Kraft, Edward Giovannucci, Kathryn L. Penney, Lorelei A. Mucci
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Family history of prostate cancer is one of the few universally accepted risk factors for prostate cancer. How much an assessment of inherited polygenic risk for prostate cancer adds to lifetime risk stratification beyond family history is unknown. Experimental Design: We followed 10,120 men in the Health Professionals Follow-up Study with existing genotype data for risk of prostate cancer and prostate cancer–specific death. We assessed to what extent family history of prostate or breast cancer, combined with a validated polygenic risk score (PRS) including 269 prostate cancer risk variants, identifies men at risk of prostate cancer and prostate cancer death across the age span. Results: During 20 years of follow-up, 1,915 prostate cancer and 166 fatal prostate cancer events were observed. Men in the top PRS quartile with a family history of prostate or breast cancer had the highest rate of both prostate cancer and prostate cancer–specific death. Compared with men at lowest genetic risk (bottom PRS quartile and no family history), the HR was 6.95 [95% confidence interval (CI), 5.57–8.66] for prostate cancer and 4.84 (95% CI, 2.59–9.03) for prostate cancer death. Men in the two upper PRS quartiles (50%–100%) or with a family history of prostate or breast cancer (61.8% of the population) accounted for 97.5% of prostate cancer deaths by age 75 years. Conclusions: Our study shows that prostate cancer risk stratification on the basis of family history and inherited polygenic risk can identify men at highest risk of dying from prostate cancer before age 75 years.
A dissemination-prone morphotype enhances extrapulmonary organ entry by Cryptococcus neoformans
Authors: Steven T. Denham, Brianna Brammer, Krystal Y. Chung, Morgan A. Wambaugh, Joseph M. Bednarek, Li Guo, Christian T. Moreau, Jessica C.S. Brown
Journal: Cell Host & Microbe (2022)

Environmental pathogens move from ecological niches to mammalian hosts, requiring adaptation to dramatically different environments. Microbes that disseminate farther, including the fungal meningitis pathogen Cryptococcus neoformans, require additional adaptation to diverse tissues. We demonstrate that the formation of a small C. neoformans morphotype-called "seed" cells due to their colonizing ability-is critical for extrapulmonary organ entry. Seed cells exhibit changes in fungal cell size and surface expression that result in an enhanced macrophage update. Seed cell formation is triggered by environmental factors, including C. neoformans' environmental niche, and pigeon guano with phosphate plays a central role. Seed cells show the enhanced expression of phosphate acquisition genes, and mutants unable to acquire phosphate fail to adopt the seed cell morphotype. Additionally, phosphate can be released by tissue damage, potentially establishing a feed-forward loop of seed cell formation and dissemination. Thus, C. neoformans' size variation represent inducible morphotypes that change host interactions to facilitate microbe spread.
A Nanozyme‐Immobilized Hydrogel with Endogenous ROS‐Scavenging and Oxygen Generation Abilities for Significantly Promoting Oxidative Diabetic Wound Healing
Authors: Zuhao Li, Yue Zhao, Hanwei Huang, Changru Zhang, He Liu, Zhonghan Wang, Mingjie Yi, Neng Xie, Yuling Shen, Xiangzhong Ren, Jincheng Wang, Jinwu Wang
Journal: Advanced Healthcare Materials (2022)

Abstract Non‐healing wound is a common complication of diabetic patients associated with high morbidity and mortality. Engineered therapeutic hydrogels have enviable advantages in tissue regeneration, however, they are suboptimal for the healing of diabetic wounds characterized by reactive oxygen species (ROS) accumulation and chronic hypoxia. Here, a unique biological metabolism‐inspired hydrogel, for ameliorating this hostile diabetic microenvironment, is presented. Consisting of natural polymers (hydrazide modified hyaluronic acid and aldehyde modified hyaluronic acid) and a metal–organic frameworks derived catalase‐mimic nanozyme ( ε ‐polylysine coated mesoporous manganese cobalt oxide), the engineered nanozyme‐reinforced hydrogels can not only capture the endogenous elevated ROS in diabetic wounds, but also synergistically produce oxygen through the ROS‐driven oxygen production ability. These fascinating properties of hydrogels protect skin cells (e.g., keratinocytes, fibroblasts, and vascular endothelial cells) from ROS and hypoxia‐mediated death and proliferation inhibition. Diabetic wounds treated with the nanozyme‐reinforced hydrogels highlight the potential of inducing the macrophages polarization from pro‐inflammatory phenotype (M1) to anti‐inflammatory subtype (M2). The hydrogel dressings demonstrate a prominently accelerated healing rate as shown by alleviating the excessive inflammatory, inducing efficiently proliferation, re‐epithelialization, collagen deposition, and neovascularization. This work provides an effective strategy based on nanozyme‐reinforced hydrogel as a ROS‐driven oxygenerator for enhancing diabetic wound healing.
Polydopamine‐Engineered Theranostic Nanoscouts Enabling Intracellular HSP90 mRNAs Fluorescence Detection for Imaging‐Guided Chemo–Photothermal Therapy
Authors: Geng Yang, Mengyue Li, Ting Song, Xiangyan Chen, Hanxi Zhang, Xiaodan Wei, Ningxi Li, Tingting Li, Xiang Qin, Shun Li, Fengming You, Chunhui Wu, Wei Zhang, Yiyao Liu, Hong Yang
Journal: Advanced Healthcare Materials (2022)

The combination of photothermal therapy (PTT) and chemotherapy is considered a promising tumor treatment modality, nevertheless, cellular resistance induced by heat shock proteins (HSPs) overexpressed in tumor cells will restrict the therapeutic effect. Herein, a multifunctional nanobeacon DOX/HCuS@PDA-MB (D/CP-MB) with a scout function for HSP90 mRNA fluorescence detection and near-infrared (NIR) triggered drug release for sensitizing chemo-photothermal therapy, is proposed. In the theranostic nanobeacons, HSP90MBs not only enable fluorescence detection of intracellular HSP90 mRNAs, but also downregulate the expression of HSP90 to reduce cell resistance. With the assistance of NIR and guidance of fluorescence imaging, spatiotemporal doxorubicin release can be achieved by the trigger of the photothermal effect, allowing for combined chemotherapy and photothermal treatment. Furthermore, the dual photothermal effect of hollow mesoporous CuS (HCuS) and polydopamine will lead to a better photothermal effect. Moreover, compared with other control groups, D/CP-MB nanobeacons exhibit effective boost therapeutic efficacy by inducing significant suppression of tumor proliferation and enhancement of apoptosis both in vitro and in vivo. In summary, this work provides novel theranostic nanobeacons that integrate imaging and therapy in a single nanoparticle, this strategy of imaging-guided therapy can enable precise tumor treatment and effectively improve tumor treatment efficacy.
A Randomized Trial of Mesenchymal Stromal Cells for Moderate to Severe Acute Respiratory Distress Syndrome from COVID-19
Authors: Michael E. Bowdish, Christina E. Barkauskas, Jessica R. Overbey, Robert L. Gottlieb, Keren Osman, Abhijit Duggal, Mary E. Marks, Jonathan Hupf, Eustace Fernandes, Bradley G. Leshnower, Jonathan L. Golob, Alexander Iribarne, Athos J. Rassias, Ellen G. Moquete, Karen O’Sullivan, Helena L. Chang, Judson B. Williams, Sam Parnia, Nirav C. Patel, Nimesh D. Desai, Andrew M. Vekstein, Beth A. Hollister, Tammie Possemato, Christian Romero, Peter C. Hou, Elizabeth Burke, Jack Hayes, Fred Grossman, Silviu Itescu, Marc Gillinov, Francis D. Pagani, Patrick T. O’Gara, Michael J. Mack, Peter K. Smith, Emilia Bagiella, Alan J. Moskowitz, Annetine C. Gelijns
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64-1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0-169.5] in cell patients and 102.0 [interquartile range, 54.0-162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.
Progressive Interstitial Lung Disease in Relatives of Patients with Pulmonary Fibrosis
Authors: Jonathan A. Rose, Maria A. Planchart Ferretto, Anthony H. Maeda, Maria F. Perez Garcia, Nikkola E. Carmichael, Swati Gulati, Mary B. Rice, Hilary J. Goldberg, Rachel K. Putman, Hiroto Hatabu, Benjamin A. Raby, Ivan O. Rosas, Gary M. Hunninghake
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Progressive Interstitial Lung Disease in Relatives of Patients with Pulmonary Fibrosis ." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp. –
Preexisting antibodies targeting SARS-CoV-2 S2 cross-react with commensal gut bacteria and impact COVID-19 vaccine induced immunity
Authors: Liqiu Jia, Shufeng Weng, Jing Wu, Xiangxiang Tian, Yifan Zhang, Xuyang Wang, Jing Wang, Dongmei Yan, Wanhai Wang, Fang Fang, Zhaoqin Zhu, Chao Qiu, Wenhong Zhang, Ying Xu, Yanmin Wan
Journal: Gut Microbes (2022)

The origins of preexisting SARS-CoV-2 cross-reactive antibodies and their potential impacts on vaccine efficacy have not been fully clarified. In this study, we demonstrated that S2 was the prevailing target of the preexisting S protein cross-reactive antibodies in both healthy human and SPF mice. A dominant antibody epitope was identified on the connector domain of S2 (1147-SFKEELDKYFKNHT-1160, P144), which could be recognized by preexisting antibodies in both human and mouse. Through metagenomic sequencing and fecal bacteria transplant, we demonstrated that the generation of S2 cross-reactive antibodies was associated with commensal gut bacteria. Furthermore, six P144 reactive monoclonal antibodies were isolated from naïve SPF mice and were proven to cross-react with commensal gut bacteria collected from both human and mouse. A variety of cross-reactive microbial proteins were identified using LC-MS, of which E. coli derived HSP60 and HSP70 proteins were confirmed to be able to bind to one of the isolated monoclonal antibodies. Mice with high levels of preexisting S2 cross-reactive antibodies mounted higher S protein specific binding antibodies, especially against S2, after being immunized with a SARS-CoV-2 S DNA vaccine. Similarly, we found that levels of preexisting S2 and P144-specific antibodies correlated positively with RBD binding antibody titers after two doses of inactivated SARS-CoV-2 vaccination in human. Collectively, our study revealed an alternative origin of preexisting S2-targeted antibodies and disclosed a previously neglected aspect of the impact of gut microbiota on host anti-SARS-CoV-2 immunity.
Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis
Authors: Hao Li, Alessia Perino, Qingyao Huang, Giacomo V.G. Von Alvensleben, Amir Banaei-Esfahani, Laura A. Velazquez-Villegas, Karim Gariani, Melanie Korbelius, Maroun Bou Sleiman, Jéromine Imbach, Yu Sun, Xiaoxu Li, Alexis Bachmann, Ludger J.E. Goeminne, Hector Gallart-Ayala, Evan G. Williams, Julijana Ivanisevic, Johan Auwerx, Kristina Schoonjans
Journal: Cell Metabolism (2022)

Bile acids (BAs) are complex and incompletely understood enterohepatic-derived hormones that control whole-body metabolism. Here, we profiled postprandial BAs in the liver, feces, and plasma of 360 chow- or high-fat-diet-fed BXD male mice and demonstrated that both genetics and diet strongly influence BA abundance, composition, and correlation with metabolic traits. Through an integrated systems approach, we mapped hundreds of quantitative trait loci that modulate BAs and identified both known and unknown regulators of BA homeostasis. In particular, we discovered carboxylesterase 1c (Ces1c) as a genetic determinant of plasma tauroursodeoxycholic acid (TUDCA), a BA species with established disease-preventing actions. The association between Ces1c and plasma TUDCA was validated using data from independent mouse cohorts and a Ces1c knockout mouse model. Collectively, our data are a unique resource to dissect the physiological importance of BAs as determinants of metabolic traits, as underscored by the identification of CES1C as a master regulator of plasma TUDCA levels.
A genetically modified minipig model for Alzheimer’s disease with SORL1 haploinsufficiency
Authors: Olav M. Andersen, Nikolaj Bøgh, Anne M. Landau, Gro G. Pløen, Anne Mette G. Jensen, Giulia Monti, Benedicte P. Ulhøi, Jens R. Nyengaard, Kirsten R. Jacobsen, Margarita M. Jørgensen, Ida E. Holm, Marianne L. Kristensen, Aage Kristian O. Alstrup, Esben S.S. Hansen, Charlotte E. Teunissen, Laura Breidenbach, Mathias Droescher, Ying Liu, Hanne S. Pedersen, Henrik Callesen, Yonglun Luo, Lars Bolund, David J. Brooks, Christoffer Laustsen, Scott A. Small, Lars F. Mikkelsen, Charlotte B. Sørensen
Journal: Cell Reports Medicine (2022)

The established causal genes in Alzheimer's disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%–3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of β-amyloid (Aβ) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD.
Quantitative Spatial Profiling of TILs as the Next Step beyond PD-L1 Testing for Immune Checkpoint Blockade
Authors: Valsamo Anagnostou, Jason J. Luke
Journal: Clinical Cancer Research (2022)

Summary Analysis of tumor-infiltrating lymphocyte (TIL) functional states, particularly tumor-reactive PD-1T TILs, within specific spatial context, can serve as a biologically informed predictive marker of immunotherapy that may be superior to standard clinical biomarkers. High-plex quantitative immune cell phenotyping within their spatial context has tremendous potential in immuno-oncology. See related article by Hummelink et al., p. 4893
VIVID: A Web Application for Variant Interpretation and Visualization in Multi-dimensional Analyses
Authors: Swapnil Tichkule, Yoochan Myung, Myo T Naung, Brendan R E Ansell, Andrew J Guy, Namrata Srivastava, Somya Mehra, Simone M Cacciò, Ivo Mueller, Alyssa E Barry, Cock van Oosterhout, Bernard Pope, David B Ascher, Aaron R Jex
Journal: Molecular Biology and Evolution (2022)

Abstract Large-scale comparative genomics- and population genetic studies generate enormous amounts of polymorphism data in the form of DNA variants. Ultimately, the goal of many of these studies is to associate genetic variants to phenotypes or fitness. We introduce VIVID, an interactive, user-friendly web application that integrates a wide range of approaches for encoding genotypic to phenotypic information in any organism or disease, from an individual or population, in three-dimensional (3D) space. It allows mutation mapping and annotation, calculation of interactions and conservation scores, prediction of harmful effects, analysis of diversity and selection, and 3D visualization of genotypic information encoded in Variant Call Format on AlphaFold2 protein models. VIVID enables the rapid assessment of genes of interest in the study of adaptive evolution and the genetic load, and it helps prioritizing targets for experimental validation. We demonstrate the utility of VIVID by exploring the evolutionary genetics of the parasitic protist Plasmodium falciparum, revealing geographic variation in the signature of balancing selection in potential targets of functional antibodies.